Design, synthesis, and bioactivity evaluation of macrocyclic benzo[b]pyrido[4,3-e][1,4]oxazine derivatives as novel Pim-1 kinase inhibitors.

Pim-1 kinase is a serine/threonine kinase which is vital in many tumors. The Pim-1 inhibitor 10-DEBC and its derivatives discovered in our previous work were modified through macrocyclization strategy. A series of benzo[b]pyridine[4,3-e][1,4]oxazine macrocyclic compounds were designed, synthesized, and evaluated as novel Pim-1 kinase inhibitors. Among these compounds, compound H5 exhibited the highest activity with an IC50 value of 35 nM. In addition, the crystal complex structure of Pim-1 kinase bound with compound H3 was determined, and the structure-activity relationship of these macrocyclic compounds was analyzed, which provides the structural basis of further optimization of novel macrocyclic Pim-1 kinase inhibitors..

Design and synthesis of cinnamic acid triptolide ester derivatives as potent antitumor agents and their biological evaluation.

A series of novel cinnamic acid triptolide ester derivatives were synthesized, and their growth inhibitory properties against human hepatoma HepG2 cells were assessed as the measure of cytotoxicity with triptolide as the positive control. One of the phenolic hydroxyl phosphorylated products, CL20 was found to possess the best cytotoxicity and surpassed the parent natural triptolide, suggesting that compound CL20 is a promising antitumor lead compound and deserves further research of pharmacological activity. In addition, the structure-activity relationship for these compounds was also investigated.

Structure-Based Optimization of 10-DEBC Derivatives as Potent and Selective Pim-1 Kinase Inhibitors.

Pim-1 kinase has been widely regarded as an attractive target for anticancer drugs. Here, we reported our continued efforts in structure-based optimization of compound 10-DEBC, a previously identified micromolar Pim-1 inhibitor. Guided by the Site Identification by Ligand Competitive Saturation (SILCS) method, we quickly obtained a series of 10-DEBC derivatives with significantly improved activity and selectivity. In particular, compound 26 exhibited an IC50 value of 0.9 nM, as well as 220- and 8-fold selectivity over Pim-2 and Pim-3 kinases, respectively.

Discovery of Novel Pim-1 Kinase Inhibitors with a Flexible-Receptor Docking Protocol.

A flexible-receptor docking protocol was designed for treating binding-site side-chain flexibility by integrating essential aspects of "Conformational Selection" and "Induced Fit" in a hierarchical fashion. Assessed in a diverse set of pharmaceutically relevant targets, this protocol showed improved performance in reproducing binding poses and ligand enrichment studies compared to rigid-receptor docking. Moreover, it has also exhibited encouraging efficiency in prospective ligand discovery for Pim-1 kinase, which led to novel Pim-1 inhibitors with single-digit nanomolar potencies.